Agouti and Agouti-related protein (AGRP) are two examples of endogenous negative regulators of the melanocortin system. Although the ability of these proteins to directly antagonize melanocortin (MC) receptors is firmly established, the physiological roles they play beyond pigmentation and regulation of food intake are still poorly understood. Recently we have shown that the dynorphin class of opioid peptides and a number of non-opioid metabolites lacking Tyr(1), can also antagonize MC receptors in vitro. The physiological and pathological significance these interactions may have in vivo, if any, also remains undetermined at this time. We have synthesized analogs of dynorphin(6-12) known to possess anti-inflammatory properties in rat models of heat-induced edema and which are also capable of patently antagonizing MC receptors. We are examining these molecules for potential structural similarities with AGRP analogs to help identify structural features which confer receptor binding affinity and subtype specificity.